Current Drug Targets - Immune, Endocrine & Metabolic Disorders - Volume 3, Issue 4, 2003

Type 2 Diabetes Mellitus (T2DM) is an enormous global public health problem that has been increasing in scope at an astonishing pace over the past two decades. Efforts to implement nutritional and exercise recommendations in the US have not prevented an explosion of new cases. This dramatic rise in new diagnoses of T2DM is also occurring in the EU, Canada, Asia, and most of the developed world. Among the most important factors driving this recent epidemic are the increased availability of calories and the development of obesity. Current therapies for T2DM that improve glycemic control are effective at reducing both microvascular and macrovascular complications. Unfortunately, the natural history of both impaired insulin action and insulin secretion that underlie T2DM is not substantially altered by current pharmacological interventions. Indeed, the impact of single drugs to reduce hyperglycemia is often reduced over time and multiple drug regimens become necessary. This treatment paradigm entails progressive complexity, cumulative adverse effects, and increased costs that significantly limit effective control of blood glucose in the average patient. Ideal therapeutic candidates for T2DM would improve glucose homeostasis while also slowing or reversing the natural history of disease. At present, it is not clear how progression of T2DM can be slowed or reversed beyond the limited effectiveness of appropriate diet and exercise. Thus, it is imperative to identify new approaches to the effective treatment of T2DM. These need to provide novel options to safely and economically control hyperglycemia and prevent the devastating cardiovascular, renal, and ocular complications that arise. An important point of caution is that many strategies to identify therapeutic targets involve rodent models. These include the candidate gene / pathway approach, genetic screening, proteomics, and mass screening of rodent knock-out models. The premise is that developing a comprehensive understanding of the molecular defects causing insulin resistance and hyperglycemia in rodents will lead to identification of appropriate targets for intervention in T2DM in humans. An important part of validating targets identified in rodent models is to show clear relevance for T2DM in humans. Complicating this task is the fact that the clinical diagnosis of Type 2 DM is defined somewhat arbitrarily. An enormous body of work clearly documents a continuum, from the early stages of the Metabolic Syndrome, (insulin resistance, dyslipidemia, hypertension, and obesity), to the end stages of T2DM, with its vascular complications. Exploring this continuum has provided clues into the connectivity of pathways that have previously been considered distinct. For example, interactions between insulin and leptin action and resistance, the contributions of inflammation to disorders of glucose and lipid metabolism, and CNS regulation of glucose and energy homeostasis. These insights have underscored the complexity and heterogeneity of factors that contribute to T2DM and the mechanisms by which they lead to increased morbidity and mortality. The papers presented within this 'Hot Topics in DM' issue highlight a set of pathways that provide important insights into this continuum of disordered glucose and insulin homeostasis. These pathways suggest an array of exciting therapeutic targets that impact on multiple aspects of insulin / glucose dysregulation. Some of these targets may lead to drugs that prevent the development or progression of cardiovascular complications associated with T2DM. If we are fortunate, one or more of these targets may lead to the development of therapies that significantly improve or even reverse the underlying pathophysiology. The hope is to provide a more meaningful long term impact on the health and well-being of patients suffering from diabetes. I would like to thank the contributing authors for their significant efforts and insights. It will be fascinating to follow progress in these areas in the years to come.

Genome-wide scanning is a powerful tool to identify susceptible chromosome loci, however, individual chromosomal regions still have many candidate genes. Although cDNA microarray analysis provides valuable information for identifying genes involved in pathogenesis, expression levels of many genes are changed. A novel approach for identification of therapeutic targets is the combination of genome-wide scanning and the use of DNA chips, as shown in Fig. (1). Using DNA chips, we screened for secreted molecules, the expressions of which were changed in adipose tissues from mice rendered insulin resistance. Decreased expression of one of these molecules, adiponectin / Acrp30, correlates strongly with insulin resistance. Interestingly, recent genomewide scans have mapped a susceptibility locus for type 2 diabetes and metabolic syndrome to chromosome 3q27, where adiponectin gene is located. Decreasing serum adiponectin levels are associated with increased risk for type 2 diabetes. Interestingly, adiponectin was decreased in insulin resistant rodent models both of obesity and lipoatrophy, and replenishment of adiponectin ameliorated their insulin resistance. Moreover, adiponectin transgenic mice ameliorated insulin resistance and diabetes Adiponectin knockout mice showed insulin resistance and glucose intolerance. In muscle and liver, adiponectin activated AMP kinase and PPARα pathways thereby increasing β- oxidation of lipids, leading to decreased TG content, which ameliorated insulin resistance under a high-fat diet. Despite similar plasma glucose and lipid levels on an apoE deficient background, adiponectin transgenic apoE deficient mice showed amelioration of atherosclerosis, which was associated with decreased expressions of class A scavenger receptor and tumor necrosis factor α. Finally, cDNA encoding adiponectin receptors (AdipoR1 and R2) have been identified by expression cloning, which facilitates the understanding of molecular mechanisms of adiponectin actions and obesity-linked diseases such as diabetes and atherosclerosis and the designing of novel antidiabetic and anti-atherogenic drugs with AdipoR1 and R2 as molecular targets.

Obesity is closely associated with the Metabolic Syndrome, which includes insulin resistance, glucose intolerance, dyslipidemia and hypertension. The best predictor of these morbidities is not the total body fat mass but the quantity of visceral (e.g. omental, mesenteric) fat. Glucocorticoids play a pivotal role in regulating fat metabolism, function and distribution. Indeed, patients with Cushing's syndrome (a rare disease characterized by systemic glucocorticoid excess originating from the adrenal or pituitary tumors) or receiving glucocorticoid therapy develop reversible visceral fat obesity. The role of glucocorticoids in prevalent forms of human obesity, however, has remained obscure, because circulating glucocorticoid concentrations are not elevated in the majority of obese subjects. Glucocorticoid action on target tissue depends not only on circulating levels but also on intracellular concentration. Locally enhanced action of gluccorticoids in adipose tissue and skeletal muscle has been demonstrated in the Metabolic Syndrome. Evidence has accumulated that enzyme activity of 11β-hydroxysteoid dehydrogenase type 1 (11β-HSD1), which regenerates active glucocorticoids from inactive forms and plays a central role in regulating intracellular glucocorticoid concentration, is commonly elevated in fat depots from obese individuals. This suggests a role for local glucocorticoid reactivation in obesity and the Metabolic Syndrome. 11β-HSD1 knockout mice resist visceral fat accumulation and insulin resistance even on a high-fat diet. Furthermore, fat-specific 11β-HSD1 transgenic mice, those have increased enzyme activity to a similar extent seen in obese humans, develop visceral obesity with insulin and leptin resistance, dyslipidemia and hypertension. In adipocytes, both antidiabetic PPARγ agonists and LXRα agonists significantly reduce 11β-HSD1 mRNA and enzyme activity, suggesting that suppression of 11β-HSD1 in adipose tissue may be one of the mechanisms by which these drugs exert beneficial metabolic effects. Recently reported selective inhibitors of 11β-HSD1 can ameliorate severe hyperglycemia in the genetically diabetic obese mice. In summary, 11β-HSD1 is a promising pharmaceutical target for the treatment of the Metabolic Syndrome.

Obesity is currently an exceptionally common problem in humans. The last several years have produced a significant number of breakthroughs in obesity related areas of investigation. Triglycerides are considered the main form of storage of excess calories in fat. A key enzyme in the synthesis of triglycerides is acylCoA: diacylglycerol acyltransferase (DGAT). Recent studies have shown that mice deficient in this enzyme are resistant to diet induced obesity and have increased insulin and leptin sensitivity. These effects suggest that inhibition of DGAT in vivo may be a novel therapeutic target not only for obesity but also for diabetes.

The incidence of obesity has increased dramatically in recent years, making it one of the most pressing public health concerns worldwide. Obesity is commonly associated with comorbid conditions, most notably diabetes, coronary artery disease, and hypertension, and the coexistence of these diseases has been termed the Metabolic Syndrome. The identification of the hormone leptin provided a molecular link to obesity. Leptin is recognized as the central mediator in an endocrine circuit regulating energy homeostasis. Leptin administration leads to hypophagia, increased energy expenditure, and weight loss, while leptin deficiency enacts an adaptive response to starvation manifested by hyperphagia, decreased energy expenditure, and suppression of the neuroendocrine axis. While elucidation of leptin's role has permitted a more detailed view of the biology underlying energy homeostasis, most obese individuals are leptin resistant. A more complete understanding of the molecular components of the leptin pathway is necessary to develop effective treatment for obesity and the Metabolic Syndrome. The identification and role of one such component, stearoyl-CoA desaturase-1 (SCD-1), is reviewed here. Leptin's actions are not due to its anorectic effects alone. Leptin also mediates specific metabolic effects, including the potent depletion of triglyceride from liver and other peripheral tissues. To explore the molecular basis by which leptin depletes hepatic lipid, we used oligonucleotide arrays to identify genes in liver whose expression was modulated by leptin treatment. An algorithm was created that identified and ranked genes specifically repressed by leptin. The gene ranking at the top of this list was SCD-1, the rate limiting enzyme in the biosynthesis of monounsaturated fats. SCD-1 was specifically repressed during leptin-mediated weight loss, and mice lacking SCD-1 showed markedly reduced adiposity on both a lean and ob / ob background (abJ / abJ; ob / ob), despite higher food intake. abJ / abJ; ob / ob mice also showed a complete correction of the hypometabolic phenotype and hepatic steatosis of ob / ob mice, suggesting that fatty acid oxidation is enhanced in the absence of SCD-1. These findings indicate that pharmacologic manipulation of SCD-1 may be of benefit in the treatment of obesity, diabetes, hepatic steatosis, and other components of the Metabolic Syndrome.

Glycogen synthase kinase-3 (GSK-3) has perplexed signal transduction researchers since its detection in skeletal muscle 25 years ago. The enzyme confounds most of the rules normally associated with protein kinases in that it exhibits significant activity, even in resting, unstimulated cells. However, the protein is highly regulated and potently inactivated in response to signals such as insulin and polypeptide growth factors. The enzyme also displays a distinct and unusual preference for substrates that have been previously phosphorylated by other protein kinases which provides obvious opportunities for cross-talk. It's substrates are diverse and are predominantly regulatory molecules. The molecular cloning of the kinase revealed it to be encoded by two related but distinct genes. Moreover, the mammalian proteins showed remarkable similarity to a fruitfly protein isolated on the basis of its role in cell fate determination. From these humble beginnings, study of the enzyme has accrued further surprises such as its inhibition by lithium, its regulation by serine and tyrosine phosphorylation and its implication in several human disorders including Alzheimer's disease, bipolar disorder, cancer and diabetes. Most recently, small molecule inhibitors of GSK-3 have been developed and assessed for therapeutic potential in several of models of pathophysiology. The question is whether modulation of such an “involved” enzyme could lead to selective restoration of defects without multiple unwanted side effects. This review summarizes current knowledge of GSK-3 with respect to its known functions, together with an assessment of its real-life potential as a drug target for chronic conditions such as type 2 diabetes.

With the rapid increase in the number of patients developing type 2 diabetes mellitus and the lack of optimal therapies, much focus has been placed on the insulin-signaling pathway in the discovery of novel drug targets. Phosphatidyl Inositol 3-Kinase (PI3K) is central to mediating insulin's metabolic effects. PI3K catalyzes the generation of phosphatidyl inositol (3,4,5) triphosphate (PIP3). Inhibition of PI3K activity results in a blockade of insulin signaling including glucose uptake and glyocogen synthesis. Thus, PIP3 is a critical mediator of insulin action. A family of phosphatidyl inositol phosphatases have been identified that counter-regulate PI3K activity by hydrolyzing PIP3 to phosphatidyl inositol bisphosphate at either the 3' or 5' position of the inositol ring. Mice lacking one of these enzymes, Src-Homology Inositol Phosphatase-2 (SHIP2), demonstrate increased insulin sensitivity, suggesting that pharmacological inhibition of SHIP2 could alleviate insulin resistance. Recent studies demonstrate elevated SHIP2 expression is associated with insulin resistance in human patients. Comparing the studies on SHIP2 and other phosphatases suggests how inhibition of SHIP2 leads to increased insulin sensitivity without deleterious effects. This review focuses on the emergence of SHIP2 as a target in the insulin-signaling pathway for the treatment of type 2 diabetes.

Obesity is increasing at an alarming rate and is considered by the World Health Organization as one of the top 10 epidemics worldwide. Resistance to leptin and insulin are likely to play a central role in obesity; thus, blocking inhibitors of these signaling pathways could prove useful in treating this disorder. Several lines of evidence have converged on protein tyrosine-phosphatase 1B (PTP1B) as one of the most important negative regulators of leptin as well as insulin signaling. Therefore, PTP1B appears to be a promising therapeutic candidate for the treatment of obesity. In this review, we discuss the role of PTP1B in leptin and insulin signaling, as well as its potential as a drug target in the treatment of obesity.